The Local Edge Machine: inference of dynamic models of gene regulation

We present a novel approach, the Local Edge Machine, for the inference of regulatory interactions directly from time-series gene expression data. We demonstrate its performance, robustness, and scalability on in silico datasets with varying behaviors, sizes, and degrees of complexity. Moreover, we demonstrate its ability to incorporate biological prior information and make informative predictions on a well-characterized in vivo system using data from budding yeast that have been synchronized in the cell cycle. Finally, we use an atlas of transcription data in a mammalian circadian system to illustrate how the method can be used for discovery in the context of large complex networks.Department of Applied Mathematic

The IUCF Cooler Project

This research was sponsored by the National Science Foundation Grant NSF PHY 87-1440

Evaluation of a longitudinal family stress model in a population‐based cohort

The family stress model (FSM) is an influential family process model that posits that socioeconomic disadvantage impacts child outcomes via its effects on the parents. Existing evaluations of the FSM are constrained by limited measures of socioeconomic disadvantage, cross‐sectional research designs, and reliance on non‐population‐based samples. The current study tested the FSM in a subsample of the Fragile Families and Child Wellbeing Study (N = 2,918), a large population‐based study of children followed from birth through the age of nine. We employed a longitudinal framework and used measures of socioeconomic disadvantage beyond economic resources. Although the hypothesized FSM pathways were identified in the longitudinal model (e.g., economic pressure at the age of one was associated with maternal distress at the age of three, maternal distress at the age of three was associated with parenting behaviors at the age of five), the effects of socioeconomic disadvantage at childbirth on youth socioemotional outcomes at the age of nine did not operate through all of the hypothesized mediators. In longitudinal change models that accounted for the stability in constructs, multiple indicators of socioeconomic disadvantage at childbirth were indirectly associated with youth externalizing behaviors at the age of nine via either economic pressure at the age of one or changes in maternal warmth from ages 3 to 5. Greater economic pressure at the age of one, increases in maternal distress from ages 1 to 3, and decreases/increases in maternal warmth/harshness from ages 3 to 5 were also directly associated with increases in externalizing behaviors from ages 5 to 9. Results provide partial support for the FSM across the first decade of life.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163397/2/sode12446.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163397/1/sode12446_am.pd

Inhibitory Control Across the Preschool Years: Developmental Changes and Associations with Parenting

The normative developmental course of inhibitory control between 2.5 and 6.5 years, and associations with maternal and paternal sensitivity and intrusiveness were tested. The sample consisted of 383 children (52.5% boys). During four annual waves, mothers and fathers reported on their children’s inhibitory control using the Children\u27s Behavior Questionnaire. During the first wave, mothers’ and fathers’ sensitivity and intrusiveness were observed and coded with the Emotional Availability Scales. Inhibitory control exhibited partial scalar invariance over time, and increased in a decelerating rate. For both mothers and fathers, higher levels of sensitivity were associated with a higher initial level of children\u27s inhibitory control, whereas higher levels of intrusiveness predicted a slower increase in children\u27s inhibitory control

Neural cognitive control moderates the association between insular risk processing and risk-taking behaviors via perceived stress in adolescents

Adolescence is a critical period for the initiation of risk-taking behaviors. We examined the longitudinal interplay between neural correlates of risk processing and cognitive control in predicting risk-taking behaviors via stress. The sample consisted of 167 adolescents (53% males) who were assessed twice (MAgeTime1 = 14.13, MAgeTime2 = 15.05). Neural risk processing was operationalized as blood-oxygen-level-dependent (BOLD) responses in the anterior insula during a lottery choice task and neural cognitive control as BOLD responses during an inhibitory control task. Adolescents reported on perceived stress and risk-taking behaviors. Structural equation modeling analyses indicated that low insular risk processing predicted increases in perceived stress, while perceived stress did not predict changes in insular risk processing across one year. Moreover, significant moderation by neural cognitive control indicated that low insular risk processing predicted increases in risk-taking behaviors via increases in perceived stress among adolescents with poor neural cognitive control, but not among adolescents with good neural cognitive control. The results suggest that risk processing in the anterior insular cortex plays an important role in stress experience and risk-taking behaviors particularly for vulnerable adolescents with poor neural cognitive control

Gene-Environment Interaction in the Etiology of Mathematical Ability Using SNP Sets

Mathematics ability and disability is as heritable as other cognitive abilities and disabilities, however its genetic etiology has received relatively little attention. In our recent genome-wide association study of mathematical ability in 10-year-old children, 10 SNP associations were nominated from scans of pooled DNA and validated in an individually genotyped sample. In this paper, we use a ‘SNP set’ composite of these 10 SNPs to investigate gene-environment (GE) interaction, examining whether the association between the 10-SNP set and mathematical ability differs as a function of ten environmental measures in the home and school in a sample of 1888 children with complete data. We found two significant GE interactions for environmental measures in the home and the school both in the direction of the diathesis-stress type of GE interaction: The 10-SNP set was more strongly associated with mathematical ability in chaotic homes and when parents are negative

Differences in adjustment by child developmental stage among caregivers of children with disorders of sex development

<p>Abstract</p> <p>Background</p> <p>The current study sought to compare levels of overprotection and parenting stress reported by caregivers of children with disorders of sex development at four different developmental stages.</p> <p>Methods</p> <p>Caregivers (<it>N </it>= 59) of children with disorders of sex development were recruited from specialty clinics and were asked to complete the Parent Protection Scale and Parenting Stress Index/Short Form as measures of overprotective behaviors and parenting stress, respectively.</p> <p>Results</p> <p>Analyses of covariance (ANCOVAs) were conducted to examine differences between caregiver report of overprotection and parenting stress. Results revealed that caregivers of infants and toddlers exhibited more overprotective behaviors than caregivers of children in the other age groups. Further, caregivers of adolescents experienced significantly more parenting stress than caregivers of school-age children, and this effect was driven by personal distress and problematic parent-child interactions, rather than having a difficult child.</p> <p>Conclusions</p> <p>These results suggest that caregivers of children with disorders of sex development may have different psychosocial needs based upon their child's developmental stage and based upon the disorder-related challenges that are most salient at that developmental stage.</p

Parenting and child adjustment: a comparison of Turkish and English families

The links between parenting and child behaviour in cultural context have received increasing research attention. We investigated the effect of parenting on child adjustment using a multi-method design, comparing English and Turkish families. The socioeconomically diverse samples included 118 English and 100 Turkish families, each with two children aged 4–8 years. Mothers completed questionnaires as well as parent–child interaction being assessed using a structured Etch-a-Sketch task with each child separately. Children were interviewed about their relationships with their mothers using the Berkeley Puppet Interview. Multiple-group Confirmatory Analysis was used to test Measurement Invariance across groups, and a multi-informant approach was used to assess parenting. We found partial cross-cultural measurement invariance for parenting and child adjustment. Strikingly, the association between parenting and child adjustment was stronger among English families than Turkish families. Culturally distinct meanings of both parenting and child behaviour must be considered when interpreting their association

Associations among the parent–adolescent relationship, aggression and delinquency in different ethnic groups: a replication across two Dutch samples

Background: The aim of the present study is to examine whether the patterns of association between the quality of the parent-adolescent relationship on the one hand, and aggression and delinquency on the other hand, are the same for boys and girls of Dutch and Moroccan origin living in the Netherlands. Since inconsistent results have been found previously, the present study tests the replicability of the model of associations in two different Dutch samples of adolescents. Method: Study 1 included 288 adolescents (M age = 14.9, range 12-17 years) all attending lower secondary education. Study 2 included 306 adolescents (M age = 13.2, range = 12-15 years) who were part of a larger community sample with oversampling of at risk adolescents. Results: Multigroup structural analyses showed that neither in Study 1 nor in Study 2 ethnic or gender differences were found in the patterns of associations between support, autonomy, disclosure, and negativity in the parent-adolescent relationship and aggression and delinquency. The patterns were largely similar for both studies. Mainly negative quality of the relationship in both studies was found to be strongly related to both aggression and delinquency. Discussion: Results show that family processes that affect adolescent development, show a large degree of universality across gender and ethnicity

Inhibition of nuclear factor kappa-B signaling reduces growth in medulloblastoma in vivo

Abstract Background Medulloblastoma is a highly malignant pediatric brain tumor that requires surgery, whole brain and spine irradiation, and intense chemotherapy for treatment. A more sophisticated understanding of the pathophysiology of medulloblastoma is needed to successfully reduce the intensity of treatment and improve outcomes. Nuclear factor kappa-B (NFκB) is a signaling pathway that controls transcriptional activation of genes important for tight regulation of many cellular processes and is aberrantly expressed in many types of cancer. Methods To test the importance of NFκB to medulloblastoma cell growth, the effects of multiple drugs that inhibit NFκB, pyrrolidine dithiocarbamate, diethyldithiocarbamate, sulfasalazine, curcumin and bortezomib, were studied in medulloblastoma cell lines compared to a malignant glioma cell line and normal neurons. Expression of endogenous NFκB was investigated in cultured cells, xenograft flank tumors, and primary human tumor samples. A dominant negative construct for the endogenous inhibitor of NFκB, IκB, was prepared from medulloblastoma cell lines and flank tumors were established to allow specific pathway inhibition. Results We report high constitutive activity of the canonical NFκB pathway, as seen by Western analysis of the NFκB subunit p65, in medulloblastoma tumors compared to normal brain. The p65 subunit of NFκB is extremely highly expressed in xenograft tumors from human medulloblastoma cell lines; though, conversely, the same cells in culture have minimal expression without specific stimulation. We demonstrate that pharmacological inhibition of NFκB in cell lines halts proliferation and leads to apoptosis. We show by immunohistochemical stain that phosphorylated p65 is found in the majority of primary tumor cells examined. Finally, expression of a dominant negative form of the endogenous inhibitor of NFκB, dnIκB, resulted in poor xenograft tumor growth, with average tumor volumes 40% smaller than controls. Conclusions These data collectively demonstrate that NFκB signaling is important for medulloblastoma tumor growth, and that inhibition can reduce tumor size and viability in vivo. We discuss the implications of NFκB signaling on the approach to managing patients with medulloblastoma in order to improve clinical outcomes.</p